Dr. Catherine Verfaillie, a University of Minnesota scientist, has tried to ﬁnd a replacement for embryonic stem cells.
(AP File Photo)

From adult stem cells comes debate

Hope, frustration surround research

By Gareth Cook, Globe Staff | November 1, 2004

David Prentice, a senior fellow with the Family Research Council, appeared before a Senate committee this fall to share some good news about stem cells.

Around the world scientists are pouring into the field, because human embryonic stem cells have the power to become any cell in the body, offering the promise of dramatic scientific and medical advances. The work, however, requires destroying days-old human embryos, which critics say is tantamount to taking lives. Whether the government should fund this research has become the focus of a bitter political standoff, and a key issue in the presidential campaign.

Yet when Prentice went before the senators, he offered a dramatic solution to the dilemma. There have been ''a wealth of scientific papers published over the last few years" showing that adult stem cells, which can be obtained without destroying an embryo, have virtually the same qualities as embryonic stem cells, he testified. The important science can go forward, he said, but without the need for either embryonic stem cells or the controversy.

This has become a key assertion -- in editorials, in debates, on antiabortion websites -- of opponents of embryo research, but most stem cell specialists say it is simply wrong. A wave of recent experiments has cast grave doubts on the ability of adult stem cells to become a wide range of cells.

The most impressive and often-cited example is a set of adult stem cell experiments conducted in Minnesota that are surrounded by questions because, two years later, other scientists have not been able to replicate the work. The scientist who did that work, Dr. Catherine Verfaillie of the University of Minnesota, said she has not found a replacement for embryonic stem cells and is frustrated with the increasing politicization of the issue.

''My research is being misused depending on the point someone wants to get across," Verfaillie said. ''They have put words in my mouth."

Her experiment is perhaps the starkest example, but in the national stem cell debate, both sides have distorted the science. Democratic presidential candidate John F. Kerry has repeatedly assailed President Bush for a ban on stem cell research, even though the president supports stem cell research and his restrictions apply only to federal money for one type of cell, human embryonic stem cells, and only those created after August 9, 2001. Kerry supports expanding federal funding for human embryonic stem cell research and opposes limiting the research to old batches of the cells.

The distortions are fueled, in part, by the sheer complexity of the topic. Yet scientists say that the deepest source of public confusion is the fact that the political debate is being waged long before scientists know the answers to many of the most basic questions in stem cell biology, much less which avenues will result in actual treatments.

The great promise of stem cell research is that it will lead to cures for degenerative diseases, such as Parkinson's or juvenile diabetes, that affect many millions of Americans. Yet the science is just too new to say what diseases might be helped more by adult or embryonic stem cell research or by neither.

For decades, doctors have been transplanting bone marrow, which contains adult stem cells that form the cells in the blood, to treat certain cancers and other immune and blood-related diseases, such as sickle cell anemia. But scientists are far from showing that adult stem cells can treat a wide range of other diseases.

Embryonic stem cells, by contrast, have the natural ability to become any type of cell in the body and offer a unique tool for understanding human development. But scientists have only just begun to experiment with human embryonic stem cells, which were discovered in 1998. Embryonic stem cells are not currently used to treat anything, and there are many fundamental technical hurdles that lie between today's science and the potential medicine of tomorrow.

Prentice, a former biology professor at Indiana State University, defended his Senate testimony, saying that he was delivering facts about research that has been obscured by the attention given to embryonic stem cells. And most stem cell specialists agree that adult stem cells are a vital area of research, underappreciated by the public, that could lead to a wealth of new treatments.

''We need both" kinds of research, said Dr. Leonard Zon, a researcher at Children's Hospital Boston and president of the International Society for Stem Cell Research. ''Advances in one field help the other."

The public, understandably, wants to hear about cures for the scourge of degenerative diseases. Scientists would like nothing more than to find these cures. But, Zon and other scientists said, the history of medical research is very clear on one point: Nobody can say today whether any particular advance is the first step toward revolutionary treatments or an alluring dead end.

Hope, then frustrationVerfaillie can remember the thrill that came over her in her laboratory as she realized that she might have a spectacular discovery on her hands, the kind of huge, surprising leap forward that can lead to a Nobel Prize.

It was 1998, and Verfaillie's research team had apparently stumbled across an entirely unexpected kind of stem cell. Taken from bone marrow, in the soft core of bones, it was an adult stem cell that seemed to hold the potential to develop into virtually any tissue in the body, a power that scientists previously believed could be found only in stem cells harvested from human embryos.

In 2002, when the results became public, they caused a sensation. If verified, these new cells might give doctors the ability to repair a wide variety of tissues without the ethical questions that bedevil embryonic work. Other scientists have since made similar assertions, but Verfaillie's work is the most scientifically established.

What has amazed researchers about Verfaillie's stem cells, which she has dubbed the multipotent adult progenitor cell, is that they seem to contradict longstanding principles of developmental biology. Beginning with a batch of stem cells thought to make only tissues such as bone, cartilage, and fat, Verfaillie was able to coax some of the cells, the MAPCs, into becoming surprising tissues, such as brain and liver.

Scientists believe that the cells of the body form a kind of family tree, with the embryonic stem cell at the trunk and most of the multitude of cells that make up the body at the tips of the branches. In the very beginning, when a human embryo is just days old, the body begins its development as a formless mass of cells that are called pluripotent, because they have the potential to become any cell. When these cells are removed from an embyro and grown in a laboratory dish, they are referred to as embryonic stem cells.

Then, as the embryo develops, different cells start to travel down different branches in the family of cells, becoming more specialized, and less flexible, in a process called commitment. Stem cells that are partway down one of these branches are called adult stem cells, because they are destined to become specific types of tissue in the adult and are thought to have lost the full potential of embryonic stem cells.

Thus, there are many kinds of adult stem cells, each capable of repairing only the tissue they are destined to become. However, researchers have isolated only a limited number of types of adult stem cells, and some organs may lose all of their adult stem cells by the time they have finished developing, meaning that adult stem cells could not be used to treat those organs.

Around the time that Verfaillie was doing her initial research, other scientists began publishing papers that challenged this paradigm, arguing instead that seemingly committed adult stem cells could naturally transform themselves into types of cells in distant parts of the cellular family tree, giving the body a hitherto unrecognized power to regenerate.

But more recent experiments, in some cases by the same scientists, have reversed most of these findings. In 2001, for example, a stunning paper in the journal Nature indicated that bone marrow cells could transform into heart muscle, offering hope for treating heart disease. But this spring, two papers in the same journal suggested that the original research was wrong. Similar claims for bone marrow cells transforming into brain cells, liver cells, and others have also been reversed.

''To be frank, I really wanted it to be true," said Dr. Irving Weissman of Stanford University, one of the founding fathers of stem-cell science and cofounder of two companies that work with adult stem cells. ''But everywhere we have looked, [the claims] just fell apart."

Verfaillie's work is different from many of these claims, however, because she heavily processes her cells for many weeks before she does her experiments. She begins with cells from the bone marrow, but then puts them in lab dishes where the cells can grow and multiply. Then, for more than a month, she repeatedly transfers the cells from one lab dish to another to prevent the cells from growing too densely.

This process seems to slowly kill off most kinds of cells, but leaves behind a population of the special cells she wants, something like burning down a haystack to find the needle. Yet, even in the hands of her team, Verfaillie said, the method works less than half of the time.

Only a handful of other laboratories have been able to get the method to work and only after intensive consultation with Verfaillie, including lengthy onsite visits. And no outside laboratory has been able to replicate one of the most impressive experiments she described in 2002, in which one of the cells was injected into a mouse embryo and then was shown to have yielded cells in many of the animal's tissues. Weissman and other scientists said that Verfaillie's research could be very important and may even lead to new medical cures, but that the failure of other laboratories to replicate the work raises questions, and makes it difficult to understand what the cells are, and what they are capable of.

Verfaillie said that she shares these concerns, and she has been working hard to help other laboratories with the cells. Weissman's lab has been trying to replicate the work, so far without success.

Although Verfaillie's work has received more attention, there are other sources of adult stem cells that some scientists suspect may have more potential to form a variety of cells than previously thought, such as blood from a newborn's umbilical cord, or even stem cells from a fetus that circulate in the mother's body, which were identified by Dr. Diana Bianchi, who is the vice chairwoman for pediatric research at the Floating Hospital for Children at Tufts-New England Medical Center.

None of these cells has been shown to be as versatile or as easy to work with in a laboratory as embryonic stem cells, and none has been shown to make all types of tissue, whereas 20 years of research in mice has proved this is true for embryonic stem cells, according to Dr. George Q. Daley, who is the author of several prominent scientific papers on stem cell research and is an associate professor at Harvard Medical School and Children's Hospital.

But in the pitched battle over the future of embryonic stem cell research, these distinctions are blurred.

Before the President's Council on Bioethics issued a report on stem cells in January, there were tense fights among council members over how to present the differences between adult and embryonic stem cells, said Elizabeth H. Blackburn, a prominent cell biologist who was later fired from the council. The report's treatment of the science seemed confusing by design, Blackburn said, and treated well-established facts about embryonic stem cells on an equal footing with Verfaillie's research and other less substantiated, and even more controversial, claims.

''You could read this chapter and have no idea why scientists are making such a fuss" about human embryonic stem cells, said Blackburn, a professor at the University of California at San Francisco, who said many of her suggestions to clarify the text were ignored.

Last month, the United States Conference of Catholic Bishops launched a nationwide, two-week print ad campaign promoting adult stem cell research over embryonic stem cell research, which the organization opposes on moral grounds. One of the ads declares that ''adult stem cells have helped thousands of people, including patients with Parkinson's disease, spinal cord injury, sickle-cell anemia, heart damage and many other conditions."

Scientists interviewed by the Globe said this statement is misleading because it implies that adult stem cells are proven treatments for all of these conditions. Initial studies in humans have shown some promise with using bone marrow to treat the heart and its circulation. But, while there is potential for the future, there have been no published, controlled human studies showing bone marrow or any adult stem cell can help with Parkinson's, spinal cord injury, or any other neurological disorders, said Dr. Jeffrey D. Macklis, an adult stem cell researcher who is the director of the Massachusetts General Hospital-Harvard Medical School Center for Nervous System Repair.

Richard Doerflinger, deputy director of the Secretariat for Pro-Life Activities at the US Conference of Catholic Bishops, said the ad is not misleading and refers to one Parkinson's patient treated in California and a limited number of spinal cord injury patients treated in Portugal.

But Dr. Michel Levesque, a neurosurgeon based at the Cedars-Sinai Medical Center in Los Angeles who treated the Parkinson's patient referred to by Doerflinger, said that though his solitary patient has improved, the ad is misleading because he is only now putting together a comprehensive study of the procedure and has not proven it is an effective treatment.

Both sides of the debate have tried to earn political advantage by implying that research is closer to generating cures than it is. Proponents of embryonic stem cell research often say that 100 million or more Americans might be helped, though nobody can say what the work will yield or when.

For Verfaillie and many other scientists, it has been a difficult spectacle to behold. Embryonic stem cell research raises deep ethical questions, but on purely scientific grounds most researchers agree that both adult and embryonic stem cell research are promising, and they cringe to see one played off against the other.

Sitting in her 14th-floor office with a view of the Minnesota Metrodome in the distance, Verfaillie said that the last several years have been both exhilarating and maddening. Her lab has doubled in size, with federal funding, and she has found fascinating new biological territory to explore.

''I have also learned," said Verfaillie, ''that politics can't be influenced by scientific facts very much."